Positron emission tomography (PET) is a nuclear medicine imaging technique for studying metabolic and physiological processes and tissue microenvironments, and diagnosing or treating diseases including cancer, heart disease and brain abnormalities. PET uses non-toxic radiopharmaceutical agents formed from biologically relevant molecules labelled with positron-emitting radionuclides. Following administration to the body, the radiopharmaceutical agent localizes within the tissue of interest. When the isotope decays, it emits a positron which then annihilates with an electron of a nearby atom, producing gamma rays. The PET scanner detects gamma ray photons, thereby producing an image of the tissue for interpretation by a radiologist.
Due to its emission of positrons and half-life of 110 minutes, fluorine-18 (18F) is a widely accepted radionuclide for PET, and is commonly synthesized into fluorodeoxyglucose (FDG) to form 2-deoxy-2-[18F] fluoro-D-glucose (18F-FDG). FDG is a sugar compound which is processed by growing cancer cells, the brain, and cardiac muscles. Transport of sugar through cell membranes requires transport proteins known as GLUTs. Imaging tumours with PET traditionally uses [18F]-FDG as the imaging agent to take advantage of the characteristic overexpression of facilitated hexose transporter isoform GLUT1 (SLC2A1) in certain cancerous cells. [18F]-FDG is subsequently trapped and accumulated within the cells as a result of phosphorylation at the 6-position by hexokinase II, an enzyme which is overexpressed in many cancers (Santiago et al., 2006; Buerkle, 2008; Hamberg et al., 1994; and Mavi et al., 2006). [18F]-FDG has been used to evaluate metastatic and recurring cancer, and to detect the primary disease (Eubank et al., 2005; Kumar et al., 2004; Santiago et al., 2006; Schirmer et al., 2003; Weir et al., 2005).
In breast cancer, it is widely recognized that the Class II hexose transporter GLUT5, which can readily move fructose across the cell membrane, is more highly expressed in transformed breast tissue compared to normal, untransformed tissue (Zamora-Leon et al., 1996; Godoy et al., 2006; Ponten et al., 2008). Not only is GLUT5 overexpressed, but the Class I glucose/fructose-transporting isoform GLUT2 is also overexpressed in cancerous breast tissue, which likely contributes to increased fructose uptake in these tumoural cells. The increased expression of both GLUT5 and GLUT2 may be indicative of the cells' broadening their substrate preference to compensate for an increased demand for metabolic fuel. This theory is supported by the observed ability of anti-sense oglionucleotide induced knockdown of GLUT5 to decrease the proliferation of breast cancer cells in vivo (Chan et al., 2004). The knowledge that breast cancers exhibit overexpression of GLUT5 and GLUT2 suggests that an [18F]-labelled fructose analogue may have potential for the imaging and diagnosis of these tumours (Zamora-Leon et al., 1996; Godoy et al., 2006; and Haradahira et al., 1995). [18F]-FDG is inefficiently transported by GLUT-2 and not at all by GLUT-5, and thus will be poorly taken up by breast cancers that overexpress these transporters over GLUT-1. Radiolabelled fructose analogues which are targeted to the Class II fructose-transporting GLUT5 and the Class I glucose/fructose-transporting GLUT2 may reveal a new avenue for improved imaging of breast and other cancers with similar GLUT expression profiles.
[18F]-FDG-PET is ineffective in the detection of small tumours and more differentiated sub-types such as tubular carcinomas or lobular carcinomas (Kumar et al., 2004; Buck et al., 2002; Crippa et al., 1998). 18F-FDG also accumulates in areas of inflammation, making it difficult to distinguish between cancerous and inflamed tissues upon imaging. Macrophages and other immune cells have been implicated in the generation of false positives when using [18F]-FDG-PET due to increased uptake of large quantities of glucose and [18F]-FDG by these cells (Buck et al., 2002; Fu et al., 2004). Macrophages are strongly associated with tumour sites and contribute a large percentage of the total tumoural cell count, especially after treatment with chemotherapeutics when macrophage numbers actually increase due to the destruction of tumoural cells. This phenomenon can be responsible for an increase in the observed [18F]-FDG uptake by PET, generating false-positives in images used to monitor treatment efficacy (Schirmer et al., 2003; Kubota et al., 1994).
The stages for PET imaging generally involve radionuclide production in a cyclotron, synthesis of a precursor, radiolabelling in a radiotracer laboratory, purification, administration to a subject, a PET scan, and image analysis and evaluation. PET chemistry with 18F must be completed rapidly preferably within an hour to provide sufficient radioactive tracer for a PET scan. The preparation of imaging radiopharmaceuticals using 18F as a PET radionuclide requires rapid high yield reactions which can be accomplished by the preparation of suitable precursor molecules. Preparation of suitable precursors can be difficult and time consuming.
There is a need for methods and reagents for facilitating the efficient syntheses of fructose-based radiopharmaceuticals for PET. Further, fructose-based radiopharmaceuticals which improve contrast between cancerous and inflamed tissues, and enhance diagnostic imaging of breast cancer cells are desirable.